Regional fat depot masses are influenced by protein-coding gene variants.

Waist-to-hip ratio (WHR) is a prominent cardiometabolic risk factor that increases cardio-metabolic disease risk independently of BMI and for which multiple genetic loci have been identified. However, WHR is a relatively crude proxy for fat distribution and it does not capture all variation in fat distribution. We here present a study of the role of coding genetic variants on fat mass in 6 distinct regions of the body, based on dual-energy X-ray absorptiometry imaging on more than 17k participants. We find that the missense variant CCDC92S70C, previously associated with WHR, is associated specifically increased leg fat mass and reduced visceral but not subcutaneous central fat. The minor allele-carrying transcript of CCDC92 is constitutively more highly expressed in adipose tissue samples. In addition, we identify two coding variants in SPATA20 and UQCC1 that are associated with arm fat mass. SPATA20K422R is a low-frequency variant with a large effect on arm fat only, and UQCC1R51Q is a common variant reaching significance for arm but showing similar trends in other subcutaneous fat depots. Our findings support the notion that different fat compartments are regulated by distinct genetic factors.